Tissue-specific regulation of Ca2+ channel protein expression by sex hormones

The L-type Ca²⁺ channel pore-forming α subunit, α_1C can be detected in brain and heart as two proteins with molecular masses of ∼240 kDa and ∼190 kDa known as α_1C-long and α_1C-short, respectively. In brain, the α_1C-short is thought to be the product of a ∼50 kDa C-terminus calpain-mediated proteolytic deletion. We now show that uterine smooth muscle also possesses α_1C-long and α_1C-short isoforms, and that the relative expression of these two forms is regulated by sex hormones in a tissue-specific manner. Protein expression of α_1C L-type Ca²⁺ channels was examined in uterine smooth muscle, brain and heart, comparing non-pregnant (NP) estrus vs. late-pregnant (21 days) rats. The two forms of α_1C were detected in all studied tissues. In late-pregnant uterus, α_1C-long doubled the expression of α_1C-short; in NP uterus the opposite occurred. However, these changes were restricted to the uterine muscle, with no changes in brain and heart. To investigate the mechanism of such regulation, ovariectomized rats were treated with sex hormones, progesterone (P4) and/or 17β-estradiol (estrogen, E2). P4 treatment, which yielded P4 plasma levels of 5±1 ng/ml and a high P4/E2 ratio (3±1.5×10³) similar to the ratio in late-pregnant uterus (1.5±0.3 ×10³), facilitated α_1C-long expression. In contrast, E2 or E2+P4 treatment that increased E2 plasma levels to 60±8 pg/ml and 75±24 pg/ml, produced low P4/E2 ratios of 0.03±0.006 and 0.2±0.1, respectively. These low P4/E2 ratios also found in NP rats at estrus (0.3±0.1) favored the expression of α_1C-short form in myometrium. Neither hormone treatment altered α_1C expression in brain or heart. Our results indicate that expression of α_1C isoforms depends on P4/E2 ratios. Plasma P4/E2 ratios <1×10³ favor the expression of the α_1C-short; whereas ratios >1×10³ facilitate the expression of the α_1C-long form. This regulation is tissue-specific for myometrium since it did not occur in heart and brain tissues.     

Does nitric oxide contribute to the basal vasodilation of pregnancy in conscious rabbits?

Pregnancy produces marked systemic vasodilation, but the mechanism is unknown. Experiments were performed in conscious rabbits to test the hypotheses that increased nitric oxide (NO) production contributes to the increased vascular conductance, but that the contribution varies among vascular beds. Rabbits were instrumented with aortic and vena caval catheters and ultrasonic flow probes implanted around the ascending aorta, superior mesenteric artery, terminal aorta, and/or a femoral artery. Hemodynamic responses to intravenous injection of N(omega)-nitro-L-arginine (L-NA; 20 mg/kg or increasing doses of 2, 5, 10, 15, and 20 mg/kg) were determined in rabbits first before pregnancy (NP) and then at the end of gestation (P). L-NA produced similar increases in arterial pressure between groups, but the following responses were larger (P < 0.05) when the rabbits were pregnant: 1) decreases in total peripheral conductance [-3.7 +/- 0.3 (NP), -5.0 +/- 0.5 (P) ml x min(-1) x mmHg(-1)], 2) decreases in mesenteric conductance [-0.47 +/- 0.05 (NP), -0.63 +/- 0.07 (P) ml x min(-1) x mmHg(-1)], 3) decreases in terminal aortic conductance [-0.43 +/- 0.05 (NP), -0.95 +/- 0.19 ml x min(-1) x mmHg(-1) (P)], and 4) decreases in heart rate [-41 +/- 4 (NP), -62 +/- 5 beats/min (P)]. Nevertheless, total peripheral and terminal aortic conductances remained elevated in the pregnant rabbits (P < 0.05) after L-NA. Furthermore, decreases in cardiac output and femoral conductance were not different between the reproductive states. We conclude that the contribution of NO to vascular tone increases during pregnancy, but only in some vascular beds. Moreover, the data support a role for NO in the pregnancy-induced increase in basal heart rate. Finally, unknown factors in addition to NO must also underlie the basal vasodilation observed during pregnancy.     

Alterations in basal glucose metabolism during late pregnancy in the conscious dog

We assessed basal glucose metabolism in 16 female nonpregnant (NP) and 16 late-pregnant (P) conscious, 18-h-fasted dogs that had catheters inserted into the hepatic and portal veins and femoral artery approximately 17 days before the experiment. Pregnancy resulted in lower arterial plasma insulin (11 +/- 1 and 4 +/- 1 microU/ml in NP and P, respectively, P < 0.05), but plasma glucose (5.9 +/- 0.1 and 5.6 +/- 0.1 mg/dl in NP and P, respectively) and glucagon (39 +/- 3 and 36 +/- 2 pg/ml in NP and P, respectively) were not different. Net hepatic glucose output was greater in pregnancy (42.1 +/- 3.1 and 56.7 +/- 4.0 micromol. 100 g liver(-1).min(-1) in NP and P, respectively, P < 0.05). Total net hepatic gluconeogenic substrate uptake (lactate, alanine, glycerol, and amino acids), a close estimate of the gluconeogenic rate, was not different between the groups (20.6 +/- 2.8 and 21.2 +/- 1.8 micromol. 100 g liver(-1). min(-1) in NP and P, respectively), indicating that the increment in net hepatic glucose output resulted from an increase in the contribution of glycogenolytically derived glucose. However, total glycogenolysis was not altered in pregnancy. Ketogenesis was enhanced nearly threefold by pregnancy (6.9 +/- 1.2 and 18.2 +/- 3.4 micromol. 100 g liver(-1).min(-1) in NP and P, respectively), despite equivalent net hepatic nonesterified fatty acid uptake. Thus late pregnancy in the dog is not accompanied by changes in the absolute rates of gluconeogenesis or glycogenolysis. Rather, repartitioning of the glucose released from glycogen is responsible for the increase in hepatic glucose production.     

Uteroplacental production of eicosanoids in ovine pregnancy

Dramatic cardiovascular alterations occur during normal ovine pregnancy which may be associated with increased prostaglandin production, especially of uteroplacental origin. To study this, we examined (Exp 1) the relationships between cardiovascular alterations, e.g., the rise in uterine blood flow and fall in systemic vascular resistance, and arterial concentrations of prostaglandin metabolites (PGEM, PGFM and 6-keto-PGF1 alpha) in nonpregnant (n = 4) and pregnant (n = 8) ewes. To determine the potential utero-placental contribution of these eicosanoids in pregnancy, we also studied (Exp 2) the relationship between uterine blood flow and the uterine venous-arterial concentration differences of PGE2, PGF2 alpha, PGFM, 6-keto-PGF1 alpha, and TxB2 in twelve additional late pregnant ewes. Pregnancy was associated with a 37-fold increase in uterine blood flow and a proportionate (27-fold) fall in uterine vascular resistance (p less than 0.01). Arterial concentrations of PGEM were similar in nonpregnant and pregnant ewes (316 +/- 19 and 245 +/- 38 pg/ml), while levels of PGFM and PGI2 metabolite 6-keto-PGF1 alpha were elevated 23-fold (31 +/- 14 to 708 +/- 244 pg/ml) and 14-fold (12 +/- 4 to 163 +/- 78 pg/ml), respectively (p less than 0.01). Higher uterine venous versus uterine arterial concentrations were observed for PGE2 (397 +/- 36 and 293 +/- 22 pg/ml) and 6-keto-PGF1 alpha (269 +/- 32 and 204 +/- 32 pg/ml), p less than 0.05, but not PGF2 alpha or TxB2. Although PGFM concentrations appeared to be greater in uterine venous (1197 +/- 225 pg/ml) as compared to uterine arterial (738 +/- 150 pg/ml) plasma, this did not reach significance (0.05 less than p less than 0.1). In normal ovine pregnancy arterial levels of PGI2 are increased, which may in part reflect increased uteroplacental production. Moreover the gravid ovine uterus also appears to produce PGE2 and metabolize PGF2 alpha.     

Comparative effects of 6-hydroxydopamine and alpha-adrenoceptor antagonists on intrauterine migration and spacing of blastocysts in the rat

Sympathetic nerve terminals were destroyed by administration of 6-hydroxydopamine (2 x 50 mg/kg) at 10:00 h on Days 4 and 5 of pregnancy in the rat. In the myometrium, this treatment markedly decreased noradrenaline concentrations (by 99%, P less than 0.001), demonstrating that myometrial noradrenaline is mainly originated from sympathetic nerves; therefore after 6-hydroxydopamine, the distribution and spacing of blastocysts remain unaffected throughout the uterus. Administration of phenoxybenzamine (2 x 6 mg/kg) in the morning of Days 4 and 5, or prazosin (4 x 3 mg/kg) from 12:00 h on Day 4 until 12:00 h on Day 5 disorganized the even distribution of blastocysts from the tubal end to the cervical end of the uterine horns. These results provide evidence that a noradrenergic transmission via action on myometrial post-synaptic alpha 1-adrenoceptors is involved as a regulatory mechanism of uterine motility for distribution and spacing of blastocysts in the rat uterus.     

Endothelial vasodilator production by uterine and systemic arteries. VII. Estrogen and progesterone effects on eNOS

Uterine blood flow (UBF) and uterine artery endothelial nitric oxide synthase (eNOS) expression are greatest during the follicular vs. luteal phase. 17 beta-Estradiol (E(2)beta) increases UBF and elevates eNOS in ovine uterine but not systemic arteries; progesterone (P(4)) effects on E(2)beta changes of eNOS remain unclear. Nonpregnant ovariectomized sheep received either vehicle (n = 10), P(4) (0.9 g Controlled Internal Drug Release vaginal implants; n = 13), E(2)beta (5 microg/kg bolus + 6 microg x kg(-1) x day(-1); n = 10), or P(4) + E(2)beta (n = 12). Reproductive (uterine/mammary) and nonreproductive (omental/renal) artery endothelial proteins were procured on day 10, and eNOS was measured by Western analysis. P(4) and E(2)beta alone and in combination increased (P < 0.05) eNOS expression in uterine artery endothelium (vehicle = 100 +/- 16%, P(4) = 251 +/- 59%, E(2)beta = 566 +/- 147%, P(4) + E(2)beta = 772 +/- 211% of vehicle). Neither omental, renal, nor mammary artery eNOS was altered, demonstrating the local nature of steroid-induced maintenance of uterine arterial eNOS. In the myometrial microvasculature, eNOS was increased slightly (P = 0.06) with E(2)beta and significantly with P(4) + E(2)beta. Systemic NO(x) was increased with P(4) and P(4) + E(2)beta, but not E(2)beta, suggesting differential regulation of eNOS expression and activity, since P(4) increased eNOS in uterine artery endothelium while E(2)beta and the combination further increased eNOS protein.     

Uterine artery blood flow and renal sympathetic nerve activity during exercise in rabbit pregnancy

The uterine artery blood flow (UtBF) and renal sympathetic nerve activity (SNA) responses to treadmill exercise were evaluated in 12 nonpregnant (NP) and 17 term pregnant (P) rabbits. UtBF was monitored continuously with a Transonic flowprobe. Rabbits underwent three exercise trials (5-min duration) that varied in absolute workload. The rise in renal SNA with exercise was intensity related. Pregnancy did not affect the average steady-state renal SNA response expressed relative to maximum activity (P 24 +/- 1% vs. NP 23 +/- 2% of maximum smoke-elicited activity) and increased the average renal SNA response expressed relative to resting activity (P +155 +/- 19% vs. NP +84 +/- 23% from rest, P = 0.03) At rest, UtBF (P 13 +/- 3 vs. NP 1.9 +/- 0.3 ml/min) and uterine artery conductance (UtC; P 22 +/- 5 vs. NP 2.8 +/- 0.5 ml. min-1.mmHg-1 x 10-2) were elevated in the P rabbits. The average exercise-related decreases in UtBF (P -16 +/- 4% vs. NP -48 +/- 4%) and UtC (P -27 +/- 4% vs. NP -54 +/- 4%) were attenuated in the P rabbits. Pregnancy does not impair the ability to raise renal SNA but attenuates the uterine artery constrictor response to moderate to heavy dynamic exercise in rabbits. Under normal conditions, the pregnant uterine circulatory bed may be relatively protected from exercise-related redistribution of blood flow.     

Temperature acclimation in the Mongolian gerbil (Meriones unguiculatus): biochemical and organ weight changes.

1. Adult Mongolian gerbils (Meriones unguiculatus) were acclimated to 5 +/- 1, 24 +/- 1 and 34 +/- 1 degrees C for 6-8 weeks. 2. Body weights of temperature acclimated gerbils did not differ significantly from controls. Organ wt/body wt ratios of liver, kidney and heart increased in cold-acclimated and decreased in heat-acclimated gerbils. Adrenal wt/body wt ratio increased in the cold and was unchanged in the heat. Relative weights of brain, spleen, lungs, brown fat and ovaries + uterus did not change with temperature acclimation. 3. Cold acclimation produced significant increases in specific and total activity of brown fat alpha GPO and liver SO and AAO and in total activity of kidney SO; a significant decrease in liver mitochondrial ADP/O ratio with succinate as substrate; and no change in brown fat SO or liver alpha KGO. 4. Heat acclimation produced significant decreases in specific and total activity of liver and kidney SO, and in total activity of brown fat SO and alpha GPO, and liver AAO and alpha KGO. 5. The combined biochemical and organ wt changes seen in temperature-acclimated gerbils suggest that this species is capable of altering its metabolic thermogenic potential in response to a wide range of ambient temperatures.     

Embryonic and fetal development in a commercial dam-line genotype

During depopulation of a breeding unit within Swine Graphics Enterprises, extensive data were collected and used to examine relationships among ovulation rate, the pattern of prenatal loss, and placental and fetal development. Groups of Large White x Landrace females (n=447) were slaughtered between day 20-30, 50-55 or 85-90 of gestation, with approximately equal numbers of animals representing gilts and parity 1 (G/P1), parity 2-3 (P2/3), and parity >4 (P4+). Ovulation rate and embryo number were recorded for all animals. With the exception of the G/P1 animals, embryonic and placental weight were recorded for four conceptuses per sow on day 20-30; on day 85-90 two conceptuses per sow were dissected to determine placental and fetal development. Ovulation rate (22.7 +/- 0.2 overall) was higher (P <0.05) in P2/3 (23.6 +/- 0.4) and P4+ (24.7 +/- 0.4) than in G/P1 (20.2 +/- 0.5). Embryonic/fetal survival was 61.8 +/- 2.1% at day 20-30, 50.2 +/- 2.2% at day 50-55 and 48.7 +/- 1.9% at day 85-90 and the number of surviving conceptuses was higher (P <0.05) in the P2/3 sows than in other parity groups. There was no relationship between ovulation rate and number of live embryos at day 20-30 or 85-90. At day 20-30 and 85-90, embryo weight was positively correlated with placental weight, but neither placental weight nor embryonic/fetal weight was correlated with number of viable embryos. A parity by gestation day interaction existed; placental weight for P4+ (3.42 +/- 0.43 g) was less than for P2/3 (7.55 +/- 0.40 g) at day 20-30 (P <0.0001), whereas at day 85-90, placental weight of P2/3 (209.5 +/- 8.5 g) was less (P=0.05) than both G/P1 (235.7 +/- 7.3g) and P4+ (235.4 +/- 7.1 g). At day 85-90, fetal brain weight, relative to body weight (R2=0.61, P <0.0001), and fetal brain:liver weight ratio (R2=0.35; P <0.0001) were negatively related to mean fetal weight, and brain:liver weight ratio showed a trend towards a relationship with number of viable fetuses (P=0.08). Parity also affected brain:liver weight ratio (P=0.01). Clearly, high ovulation rates in the higher parity sows have the potential to cause excessive in utero crowding of conceptuses in the post-implantation period. Even with moderate crowding, increased brain:liver weight ratios in smaller fetuses in late gestation indicate that uterine capacity impacts fetal development as well as the number of surviving fetuses.     

Effects of estradiol and progesterone on the reproductive tract and on uterine sex steroid receptors in female lambs

The effects of estradiol-17 beta (E(2)) and progesterone (P) on the reproductive tract and on uterine estrogen receptors and P receptors were studied in 2-mo-old female lambs (n = 11). On Days 0, 1 and 2, E(2) (1 ug/kg, Group E, n = 4), P (0.3 mg/kg, Group P, n = 4) or corn oil (control) vehicle (Group C, n = 3) were administered, and in Day 3 all lambs were slaughtered. Group E (n = 12) had E(2) serum concentrations (mean +/- SEM) of 43.8 +/- 2.2 pmol L , similar to that of the follicular phase; while P concentrations in Group P (n = 12) were similar (2.8 +/- 0.18 nmol L ) to those of the luteal phase of the ewe estrous cycle. The E(2) treatment increased the reproductive tract weight, while P treatment increased only the uterine weight. Both E(2) and P receptors from upper and middle uterine zones (including the myometrium, endometrium and caruncles) were determined by binding assays with tritiated hormones, dextran-charcoal separation and inverse Scatchard analysis. Both the E(2) and P treatments decreased E(2) and P receptor concentrations in upper and middle zones, although the upper zone had higher receptor concentrations than the middle zone (P < 0.01). E(2) receptor concentrations in the upper zone (mean +/- SEM, fmol mg prot) were 1236 +/- 34, 667 +/- 80 and 444 +/- 103 for Groups C, P and E, respectively. The P receptor concentrations were 2434 +/- 135, 1273 +/- 102 and 1536 +/- 213 for the same groups. The high uterine P receptor concentrations allowed P action without prior estrogen priming of female lambs. The present results suggest that E(2) and P might down-regulate their own and each other's receptors during development. The biological responses induced by E(2) and P, as measured by the reproductive tract weight, demonstrated that at an early stage of development uterine receptors are physiologically active.     

Effects of chronic beta-adrenergic blockade on exercise training in dogs

To assess the role of beta-adrenergic stimulation in cardiovascular conditioning we examined the effects of a beta-adrenergic blocker, propranolol, in mongrel dogs during an 8-wk treadmill-training program. Seven dogs were trained without a drug (NP), six were trained on propranolol 10 mg.kg-1.day-1 (P), and five served as caged controls (C). Effective beta-adrenergic blockade was documented by a decrease in peak exercise heart rate of 54 +/- 11 (SE) beats/min (P less than 0.05) and a one-log magnitude of increase in the isoproterenol-heart rate dose-response curve. Testing was performed before drug treatment or training and again after training without the drug for 5 days. Submaximal exercise heart rate decreased similarly in both NP and P (-26 +/- 4 NP vs. -25 +/- 9 beats/min P, P less than 0.05 for both) but peak heart rate decreased only with NP (-33 +/- 9 beats/min, P less than 0.05). Treadmill exercise time increased similarly in both groups: 3.4 +/- 0.6 min in NP and 3.0 +/- 0.2 min in P (both P less than 0.05). Blood volume also increased after training in both groups: 605 +/- 250 ml (26%) in NP and 377 +/- 140 ml (17%) in P (both P less than 0.05). Submaximal exercise arterial lactates were reduced similarly in both groups but peak exercise lactate was reduced more in NP (-1.4 +/- 0.3 NP vs -0.3 +/- 0.12 mmol/l P, P less than 0.05). Lactate threshold increased in both groups but the increase was greater in NP (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Release of prostaglandins and leukotrienes from the rat uterus is an early estrogenic response

The early estrogenic responses are considered to be involved in inducing embryo implantation in a progesterone (P4)-primed uterus. Because of their involvement in the process of implantation and decidualization, prostaglandins (PGs) and leukotrienes (LTs) could be the mediators of early estrogenic responses in a P4-primed uterus. Therefore, temporal effects of estrogen on the production and/or release of PGF2, PGF2 alpha, LTB4 and LTC4 by the P4-primed uterus of hypophysectomized rats were examined. Hypophysectomized mature female rats were injected for 4 days with P4 (2 mg/rat, s.c.) or with P4 plus a single injection of estradiol-17 beta (E2) (100 ng or 200 ng/rat, i.v.) on the last day of P4 treatment. In one set of experiments, animals were killed at 0.5, 2, 4, 8, 12 and 30th after the last steroid treatment. The production of PGs and Lts by uterine homogenates was measured by radioimmunoassays (RIAs). The production of PGE2 and PGF2 alpha in P4-treated animals showed peaks at 2, 6 and 12h. The superimposition of E2 on P4 treatment induced a higher production rate of PGE2 and PGF2 alpha at 0.5h and abolished the peaks induced by P4 at 2h, but not the peaks at 6 or 12h. Irrespective of the kind of steroid hormonal treatments, uterine production of LTs showed a rapid decline between 6 and 8h followed by a sharp rise at 12h. The superimposition of E2 on P4-treatment again increased the production rates of LTB4 and LTC4 at early hours, i.e. at 0.5 and 2h, respectively, as compared to P4 treatment only.     

A comparative study of estrogen receptors alpha and beta in the rat uterus.

The uterus is an important target organ for steroid hormones. The effects of these hormones are mediated via specific receptors. The aim of this study was to compare the expression, distribution, and regulation of estrogen receptor (ER) alpha and beta in the rat uterus in order to establish possible different biological roles for the two receptor forms. Ovariectomized rats were treated with either estradiol (E(2)), progesterone (P(4)), or combinations of these for 24 or 48 h. The mRNA levels were measured by solution hybridization. Distribution of the mRNAs and receptor proteins was detected by in situ hybridization and immunohistochemistry. The results showed that ERalpha is the dominating subtype in the rat uterus. E(2) seemed to increase the ERalpha mRNA level in the glandular and luminal epithelium, but it caused a decrease of the immunostaining intensity in the glandular epithelium. P(4) reduced ERalpha expression in luminal epithelium whereas no effect was seen in the glandular epithelium. E(2) or P(4) did not alter the expression of ERbeta, on either the mRNA or protein level. In conclusion, the distribution and regulation of ERalpha and ERbeta differ in the different compartments of the rat uterus. The complex uterine responses to E(2) and P(4) are directly or indirectly mediated by differential cell-specific expression of their receptors. The low expression in the uterus and the limited regulation by gonadal steroids in this study suggest that ERbeta probably plays a minor role in the regulation of uterine physiology.     

Effects of natriuretic peptides on load and myocardial function in normal and heart failure dogs

The effects on myocardial function and loading conditions of clinically relevant doses of the natriuretic peptides (NP) have not been established. The actions of single doses (100 ng x kg(-1) x min(-1) iv over 30 min) of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) were studied in conscious normal dogs and in dogs with pacing-induced heart failure. All three NP reduced end-diastolic pressure in normal dogs, and ANP and BNP reduced end-diastolic volume. In heart failure ANP and BNP reduced EDP, and ANP reduced EDV. Arterial elastance was unchanged in normal dogs and in dogs with heart failure. ANP increased end-systolic elastance (E(es)) in normal dogs, whereas BNP tended to increase E(es) (P = 0.06). In dogs with heart failure, no inotropic effect was seen. In normal dogs, all NP reduced the time constant of isovolumic relaxation (tau), and ANP and BNP reduced tau in dogs with heart failure. Increases in plasma cGMP in dogs with heart failure were blunted. The NP reduced preload and enhanced systolic and diastolic function in normal dogs. Effects of ANP and BNP on preload and diastolic function were maintained in heart failure. Lack of negative inotropic effects in heart failure supports the validity of the NP as therapeutic agents.     

Estrogen and progesterone receptors in the ovine cervix during the postpartum period

Cervical estrogen (E) and progesterone (P) receptors were characterized and quantified during the postpartum period in Corriedale ewes lambing in the late breeding season. Cervices and uteri were collected after ovariohysterectomy at 1 d (n = 2), 5 d (n = 4), 17 d (n = 2) or 30 d (n = 2) post partum. The estrogen and progesterone receptors were measured using binding assays with tritiated hormones, dextran charcoal separation and inverse Scatchard analysis. Similar kinetic parameters in cytosolic binding sites for both hormones were found in all cervical and uterine samples, indicating that the binding protein in both tissues is of the same nature. Receptor concentrations (fmol/mg cytosolic protein) in the cervix of early (1 to 5 d, n = 6) and late (17 to 30 d, n = 4) postpartum ewes were 348 +/- 66 vs 994 +/- 145 (P < 0.05) for E and 618 +/- 126 vs 1170 +/- 201 (P < 0.05) for P, respectively. These data suggest an increased synthesis of receptors, probably due to the presence of ovarian estrogen-active follicles. Cervical E and P receptor concentrations were similar or higher than those in the uterus (1.40 +/- 0.15, n = 10 and 1.51 +/- 0.19, n = 10; for E and P respectively), and these receptor ratios did not differ between the early and late postpartum period. The high ratio between cervical/uterine receptors suggests that the ovine cervix may be a very sensitive to steroid action. In conclusion, it was shown that restoration of steroid receptors during the postpartum period in the ovine cervix is similar to receptor dynamics in the uterus, and is probably associated with the recovery of ovarian cyclicity.     

Methylene blue inhibits hypoxic cerebral vasodilation in awake sheep.

Cerebral vasodilation in hypoxia may involve endothelium-derived relaxing factor-nitric oxide. Methylene blue (MB), an in vitro inhibitor of soluble guanylate cyclase, was injected intravenously into six adult ewes instrumented chronically with left ventricular, aortic, and sagittal sinus catheters. In normoxia, MB (0.5 mg/kg) did not alter cerebral blood flow (CBF, measured with 15-microns radiolabeled microspheres), cerebral O2 uptake, mean arterial pressure (MAP), heart rate, cerebral lactate release, or cerebral O2 extraction fraction (OEF). After 1 h of normobaric poikilocapnic hypoxia (arterial PO2 40 Torr, arterial O2 saturation 50%), CBF increased from 51 +/- 5.8 to 142 +/- 18.8 ml.min-1 x 100 g-1, cerebral O2 uptake from 3.5 +/- 0.25 to 4.7 +/- 0.41 ml.min-1 x 100 g-1, cerebral lactate release from 2 +/- 10 to 100 +/- 50 mumol.min- x 100 g-1, and heart rate from 107 +/- 5 to 155 +/- 9 beats/min (P < 0.01). MAP and OEF were unchanged from 91 +/- 3 mmHg and 48 +/- 4%, respectively. In hypoxia, 30 min after MB (0.5 mg/kg), CBF declined to 79.3 +/- 11.7 ml.min-1 x 100 g-1 (P < 0.01), brain O2 uptake (4.3 +/- 0.9 ml.min-1 x 100 g-1) and heart rate (133 +/- 9 beats/min) remained elevated, cerebral lactate release became negative (-155 +/- 60 mumol.min-1 x 100 g-1, P < 0.01), OEF increased to 57 +/- 3% (P < 0.01), and MAP (93 +/- 5 mmHg) was unchanged. The sheep became behaviorally depressed, probably because of global cerebral ischemia. These results may be related to interference with a guanylate cyclase-dependent mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)